Category Archives: Medications

Kidney cancer patients are stunned by their diagnosis, anxious to make a treatment decision, and simply not know what to expect. If you are struggling with the issue of surgery to remove the tumor/kidney or to start with a med, you need to read this. Deb Maskens, Kidney Cancer Patient and Patient Advocate, our guest writer isa valued member of our disease community and currently serves on the Renal Task Force for the National Cancer Institute. A series of links below will also be helpful. (My extra comments will be in italics, like this. )Welcome aboard, Deb!

As a community of kidney cancer patients, we hear from newly diagnosed patients looking for treatment options. This is written for those patients, and for patient advocates who help patients navigate through their treatment decisions.

The challenge: this clinical trial is available at many locations across the U.S. and Canada, but patients must ask about it BEFORE they have a nephrectomy. Their own doctors may be unaware of the trial and how to work with the trial centres. In many places, patients get booked for surgery prior to learning about this option. That would be too late for a trial like this–it gives a drug therapy before the surgery for a brief period. (In one of the t wo arms, there is medication before the surgery.)

Why Might Patients Consider this Trial?

For years, the standard of care for early stage kidney cancer has been to remove the tumour surgically, sometimes with the entire kidney–either a partial or full nephrectomy. That was the end of treatment and the beginning of surveillance to watch for any signs of recurrence. (And early stage tumors can be quite large–up to 7cm or about 2 3/4″.)

Now we hope to prevent a recurrence of disease. Since advanced or metastatic kidney cancer is still incurable for the vast majority of patients, this is a worthy goal. With preventive or ‘adjuvant’ treatments, maybe we can stop the disease before it gets to the lungs, liver, bones — to those places where it begins to threaten our lives. Other cancers use this approach and offer patients a real chance to avoid recurrence.

Adjuvant – and Perhaps One Step Better to Neo-Adjuvant

We’ve seen trials for “Adjuvant” (or preventative) therapy which hope to prevent recurrence (treatments given immediately after nephrectomy). But one trial goes one step better – it’s for “Neo-Adjuvant” (before nephrectomy) as well as Adjuvant (after).

Patients may want to rush to surgery to “get it out”. In reality, those tumours have generally been growing slowly, undetected for many years. Kidney cancer surgery is rarely an emergency. There is usually time for a second opinion and to check out any newer approaches.

Here’s the thought: given that the tumour cells have gone undetected and tolerated by the immune system for so long, can put those millions of cells to work and make them “show their calling cards” to our immune system before we take them out?

Combining Neo-Adjuvant and Adjuvant Treatment – PROSPER-RCC

The Phase 3 clinical trial called PROSPER-RCC (NCT03055013) is for patients whose tumors are 7cm (2 ¾”) and larger in size, but not spread beyond the kidney area. These patients are at greater risk of spread of the cancer than those with Stage I or with smaller tumors.

Based on earlier studies, nivolumab (Optivo) is now approved for advanced kidney cancer. This is a trial to test whether there is a benefit when nivolumab is given immediately before and after a nephrectomy when tumor cells might have spread outside the kidney but are too small (microscopic) to see on scans. (Typically a patient without spread of disease would not be treated, but monitored.)

The Rationale for PROSPER-RCC: Why It Might Be Helpful

Here’s what I’ve learned:

Checkpoint inhibitor treatments with PD-1 blocking drugs like nivolumab seem to work best when the immune system may be being turned off by this cellular growth pathway. Cancer is deceptively clever and some tumours can express a protein, PD-L1. This protein can turn off our immune cell responses that recognize and fight the cancer. There was a hint of this with some positive data that indicates that these drugs work best in patients whose tumors were “PD-L1 positive”. (PD means Programmed Death and PD-L Programmed Death Ligand or connector. Death to the cells, and the signalling loop that hinders the immune response.)

In theory, when the kidney tumour is in place, there are millions of cancer cells. All of those tumour cells send off multiple negative signals to the immune system to stop it from working. However, if a checkpoint inhibitor was used and stopped those blocking signals, the immune system would have a big wake-up call – e.g., lots of targets with which to build an army of T cells. In theory, these newly educated T cells would later turn into memory cells. (If the body can maintain these memory cells, they would continue to fight any return of disease.)This is much like what happens when we are exposed to certain bacteria or viruses. Once we get exposed to the bug, we don’t usually get it again. Our immune cells have learned (“immunity”) how to kill it more quickly the next time before it turns into a full blown cold. Similarly, if these anti-RCC immune cells ever see one of these tumor cells anywhere in our bodies again, they would know to attack and kill them even if there is no drug in the patient and has not been for some time.

Surgery is still the main treatment to control early stage kidney cancer. But it will also remove the majority of targets (PD-L1) that the checkpoint drug uses to rev up the immune system. Giving the checkpoint inhibitor before surgery may maximize/optimize the drug’s ability to wake up the immune system and build that T cell army.

So the surgery is important. But let’s assume a few cells might be still circulating and have gone undetected for some time. They could still show up later on a scan as an enlarged lymph node or spot somewhere. A boost of the same checkpoint inhibitor right after the surgery could then be used to remind the immune system to continue to look for those cells and kill/eliminate them when they are small. In theory, the immune system will remember what the past “trouble” was: “Hey, haven’t I seen you before?”

From what I understand, this theory worked well in mice. The checkpoint inhibitors worked better if the primary tumour was there to help provide “a target” to activate the immune system first before the tumor was removed. While we’re not mice, this makes sense, no?

Trial Design: What Really Happens to the Patient in the Trial

PROSPER-RCC will place patients randomly into two groups:

Group One gets two infusions of nivolumab before surgery (at about 28 days and 14 days before surgery). Following that nephrectomy, the patient will receive more infusions of nivolumab. This is for 9 months post-surgery altogether, with 12 more doses.

Group Two gets the usual standard of care: upfront nephrectomy, partial or radical nephrectomy, and will be followed by close observation at an expert centre.

Two arms/groups: BLUE arm with surgery and monitoring by the trial team, the standard of care; the RED arm with medication before to surgery, followed by more after the surgery.

It is important to note that no patient on this trial receives any intravenous placebo/inactive treatment. Every patient is treated. Each patient will have either the experimental treatment or the standard of care. All are under close observation at the trial centre. This trial has been designed and discussed with patient advocates and is supported by the NCI.

or call the office of the Principal Investigator, Dr. Lauren Harshman, at: 617-632-2429

Deb’s Disclaimer:

As a patient and advocate for kidney cancer patients, I have been delving into the world of clinical trials and trying to understand as much as I can. I’m not a scientist, but I am a patient with this disease, so I bring that lens, along with some abilities to translate science into understandable terms. As a volunteer, I have no financial interest in this trial or any specific medications. @DebMaskensKCC; dmaskens@rogers.com

With the headline, “Nivolumab Shows a Substantial Objective Response Rate in Refractory Non-Clear-Cell Renal Cell Carcinoma”, the article should be welcome to all of those in the in the non clear cell RCC world. Clear cell is the most common, the garden variety of renal cell carcinoma. This is welcome news, as the non clear cell patients get very little attention from the research world. Though the patient with nccRCC might interpret this as, “Good news! Now that they know what to do for me!” , it is just not the case. Rarely is the news all that good or all that simple.

Let’s back up here and lay the groundwork. Clear cellRCC, or ccRCC is the most common of about 10 RCCs. They all land in the kidney, but can vary widely. ccRCC may be about 65% to 85% of the cases of kidney cancer, with the rarer non-ccRCCs making up the rest. Maybe 15-35% of the RCCs are considered rare, with the most common Papillary Type I, Papillary Type II, chromophobe, clear cell papillary, collecting duct/Bellini’s, medullary, translocational (not to be confused with transitional, etc, etc.) and to make it still more confusing, unclassified RCC. But when the most common is described as either 65% of the whole or 85% percent, you have to question if there is clarity in that category!

Clinical trials for RCC have usually only included patients who had clear cell. The reasons are simple; it is the biggest group, the patients can be more readily found, and that is the largest group in need of the medications. But the patients with nccRCC are really also terribly underserved. Back in the day, none of us had many options beyond surgery, so little distinction was made. The prognosis was grim all around, once the cancer had spread.

But the new world of precision medicine, in its name alone, reminds us that the meds need to be developed more precisely, that they be given to the right patients at the right time. The general crap shoot or “wild-ass guessing”, as a friend says, still remains. The latest (not necessarily greatest) group of meds are the newish immune therapies. You have seen their ads, no doubt.

One of those is Opdivo or nivolumab, its research name. It tries to unblock some of the inhibiting mechanisms that prevent the immune system from doing its job, but it has been tested in trials only with clear cell patients. BUT, that does not mean that only clear cell patients are being prescribed the meds–this, thanks to the slightly wild west of the US medical system, that can truly go beyond the FDA approved medication guidelines.

This study, which will be formally presented at ASCO in June, 2017 was announced with the headline above, “Nivolumab Shows a Substantial Objective Response Rate in Refractory Non-Clear-Cell Renal Cell Carcinoma”. The researchers are NOT in charge of the headlines, so we must dig deeper and see what this study really means to the patients with nccRCC

I tried to sort out what it means–or does not mean. My quick review is that it does not give a great deal of clarity to the majority of those nccRCC patients. A more complete report may improve upon this. Based on this link, I offer the following:

http://www.practiceupdate.com/news/16132/67/10?elsca1=

“I am always concerned that these new study reports are characterized carefully. They are always more complex and incomplete than I would like. A patient in a forum says this tells of ‘good’ responses, and especially so for the non clear cell group, but s does ‘good’ really mean generally a benefit to those rarer nccRCCs? Until a fuller report emerges, I can only note the following:

There were 23 patients, from three centers, with a median age of 59. Surprisingly 30% were African -American. This may tell us that there are more African-Americans with the rarer non-clear cell RCCs, or could reflect the local population of the three centers. Only 23 patients and with a mix of diseases will never meet the statistically critical requirements to reach the level of excellent evidence–but it may be all we have at this point.

All 23 had non-clear cell, but nearly half had ‘unclassified’ RCC, quite a high rate. Usually that is considered to represent between 1 to 4% of renal tumors. Most of the rest were papillary, but they generally make up the largest percentage of nccRCCs. No distinction is made here between Papillary Type I or Type II, which are really quite different diseases. Papillary Type I and II are the most common of the uncommon, non clear cell RCCs, and are readily distinguished from each other. This would be valuable info, and wonder if this was noted in the fuller report.

Only 3 of 4 patients had nephrectomies before the trial treatment. Were 1 of 4 patients too sick to be given the standard of care of surgery or were their doctors unaware of that? How does this affect the study, and were the no nephrectomy patients from one center or with one subtype? We do not know the reason for this high rate of no surgery, and at a time in which it is clear that the removal of the tumor is a great benefit to the patient, metastatic or not.

Two-thirds had metastatic disease at the time of diagnosis. Of the total 23, 74% had a prior treatment, mostly Sutent or Votrient. Of these patients with prior treatments, 26% had TWO such treatments. Thus these patients had already received treatments that were not directly approved for their subtypes. This is not too rare in the US, where we have greater leeway from our prescribing doctor than do patients elsewhere. But how does this fit in with the relatively low rate of nephrectomies?

This report does not say how quickly they were treated, i.e., how long from initial diagnosis until treatment with Nivolumab?A patient with Papillary Type II found to have no metastatic disease at the time of diagnosis, but who received a nephrectomy, was monitored for a year or so, then went on one or more systemic therapy is quite different from the patient with an unclassified RCC, metastatic at the time of diagnosis, not given a nephrectomy, though treated quickly with Nivolumab. What can be learned when there are such wide variations in just 23 patients that would be helpful to the Papillary Type 1 patient?

The follow up period was a median of 6.5 months, which seems very short, especially when the median Progression Free Survival of the responders was 4.2 months. The median OS is not given. That certainly may reflect an ongoing study situation, or a failure to provide a longer period of follow up.

As to objective response, 6 of the 21 evaluable patients (29%) had a Partial Response, which would likely be a 30% reduction in metastases. Another 4(19%) had Stable Disease. Two of the 23 patients died, but not from the treatment. (Assume that had to be due to the disease, but certainly indicates that for nearly 10% of the patients, this was not at all effective.)

When the final analysis was done, nine patients were still receiving Nivo. Newly recruited patients might still be in treatment at that time, but those recruited earlier may have gone out of the trial at the same time. It is important to not that Nivolumab treatments were stopped in three patients due to intolerance, and six more had postponed treatment, i.e., 9 of the 23.

Certainly we need to find meds which create responses for nccRCC patients. However, I am concerned we draw any certain conclusions from this study. Indeed, it is “good” to know that the treatment was tolerable for the majority of the participants, but not so good to read that 6 of the 21 patients had to postpone treatment, and three were removed from treatment due to intolerable/toxic side effects. We also do not know which subtypes seem to have shown responses, which would have been qutie easy to report. Did the group with Papillary Type II do generally better that the majority “unclassified” group? No answer from this stury report. And in the back of my head, I keep wondering why in the world there were so many unclassified patients in this small study? Was there a standard pathology review, or could these patients been misdiagnosed by one pathologist. Typically there is a single pathologist which can standardize the reporting. Were all these patients properly diagnosed?

Just wishing there were greater clarity and hoping to get a fuller report, post ASCO.

Without a doubt, the ‘good’ that comes from this sort of report begins with the recognition that the nccRCC group is underserved by the research community> They probably have the poorest outcomes, rarely have a clear diagnosis, and must wait for the ever popular “further research is warranted.” But all must be aware that these very small observational studies must be reviewed very carefully for what they show or do not show. Again, one to watch at ASCO, but not enough to make a major change in treatment for any one with a non clear cell RCC.

PS. Does your doctor know that there are at least four subtypes of clear cell–the big ‘common’ group–which have clearly different survival patterns? Thought so.

Another new drug for those of us with ‘unresectable and advanced” kidney cancer! YEA or is is just, yea? What does this mean to the patient in this situation as he struggles to get the best treatment possible?

The approval is for Levatinib in combination with Everolimus (Afinitor) for advanced kidney cancer or unresectable (surgery not possible) kidney cancer in patients who have had previous TKI treatment–Sutent, for example. This was based on a Phase II trial, so a bit unusual in that regard. Generally the FDA waits until there is a larger Phase III trial, so this reflects the need for better second-line treatments.

It is always great to have another tool against kidney cancer, and on top of the recent approval of Nivolumab (Opdivo) and Cabozantinib (Cometryx), but do note that all three are for second line use, after the first line meds have failed. Current first line drugs include high dose interleukin, Sutent and others.

All the patients in this trial had previously used and quit responding to the first line TKIs, and are compared in three arms

Arm 1) Lenvatinib alone–52 patients—didn’t make the grade

Arm 2) Everolimus alone–51 patients—standard of care for second line

Arm 3) Lenvatinib & Everolimus in combo–51 patients–the new approval.

Not a very big trial, so harder to make broad judgements!

Everolimus is already approved for second line use, and Lenvatinib alone was NOT approved except in combination with Everolimus. With that, just ignore Arm 1. The big news is that the combo improved median Progression Free Survival (PFS) in the combo to 14.6 months vs 5.5 months with Everolimus. The median gives us the POINT in time at which half got “progressed” on their disease, ie, the damn stuff grew, while the other half had not yet had progression. Not an average, so half of the combo patients had PFS by 14.6 months, and the other combo half did not have PFS until after that time.

The median Overall Response Rate (ORR) was not very high–but quite typical–and important to understand. The combo patients had a 37% ORR, so about 1 in 3 had a measurable response. That compared to just 6% with everolimus. The most important measure to patients is median Overall Survival. This is usually measured when one-half of a patient group has died, so there are always patients who live beyond that median point. The combo OS was 25.5months vs the Evero alone OS of 15.4 months. There was no mention I could find whether there were patients alive at this point, but assume there were. Love to know if there are very long term survivors in the combo group, and what makes them more likely to have that response!

In the combo, 29% of the patients discontinued treatment due to side effects and with Everolimus alone, 12% discontinued. However, both groups had large number of reduced dosages and/or dose interruptions, 89% in the combo group, and 54% in the evero group. Read: some tough side effects.

The most serious side effect in my opinion was that renal failure occurred in 11% of patients in the combo, 5 of the 51 patients. Grouping ‘renal impairment with failure”, the combo caused such problems in 18% of those patients, 12% i the evero group. Not good news for those of us with one kidney, so something to be monitorly VERY carefully.

The other ‘usual suspects’ in the side effects in the combo were hypertension 42% vs 10%, diarrhea 81% vs 19%. Not surprising was a fairly high rate of ‘hemorrhagic events”, ie, bleeding problems in both groups, 32% vs 26%. And more.

Again, not easy, better than no treatments,or using everolimus alone. All these meds demand good communication with the treating team and patients. Sadly missing in this trial and in every other one is any real guidance as to which patients might best respond to this combo. Neither is there a neat comparison to the second-line use of Nivo or Cabo. Practice, practice, and be aware of your own health issues as to side effect potential as you look at these trials and your own situation.

http://www.multivu.com/players/English/7690031-eisai-lenvima-fda-2/ for the company’s review and videos by Dr. Sumanta Pal at the City of Hope and a spokemans from Esai.

Recent headlines called a new medication, Nivolumab, both a miracle or breakthrough and more. Is it hype or hope?Why is it so hard to sort out the reality?

Let’s go through the facts from the New England Journal of Medicine and ignore the headlines. First, its being in the NEJM is important, as it has passed review by other researchers. (Sadly missing in too many ‘breakthroughs”).

The new med, Nivolumab was compared against Everolimus, a second-line treatment. Therefore Evero is thought to be of lesser effectiveness than the first line meds. Second-line meds are generally used when others meds quit helping or their side effects are too hard. Automatically NOT the miracle cure, but another option when first-line treatments fail.

Should Nivo have been compared to the first-line meds? Being better in the first-line would be bigger deal, but we need more approved meds. Second-line treatments usually are easier to ‘beat’, as the new med must be better or less toxic. Again, more likely to be approved!

PATIENT CHARACTERISTICS

The study had 821 patients 24 countries, half using Nivo and half Evero. Patients were similar, 90% having had a nephrectomy, removing the tumor and some or all the kidney. Then the cancer spread, making metastases, (mets, for short). These patients had 1-3 treatments, first-line drugs like Sutent, a targeted therapy, and a few had used cytokines or even chemotherapy. Having had an mTOR inhibitor like Everolimus was not acceptable. Most had lung mets (67%), followed by liver(12%) and then bone mets (18%). Most with 2 or more sites of mets.

To enter the trial, the patient had to have had disease progression after their last treatment, within six months of enrolling in the trial. No doubt, some patients had greater disease progression than others, but had relatively good performance status, not completely bed-ridden or unable to function.

The median time from initial diagnosis of kidney cancer at any stage to entering the trial was 31 months; half had been diagnosed less than 31 months ago, and half more than 31 months before the trial. That range of time from diagnosis to trial was 1 to 392 months. That means that for some patients, they went a long time either fighting the disease since diagnosis, having a later recurrence, being treated, yet having disease progression years after the intial diagnosis. At least one person was diagnosed 392 months earlier. This is a good reminder to patients who have been told, “I got it all”. This darn stuff can return, so having a plan B is important. Again, the previous treatment failed and these patients got directed into this trial.

GENERAL RESULTS

Median Overall Survival (OS) is a measured when one-half of the total number in the group dies. Median OS for Nivo was 25 months with some patients still surviving at time of report, beyond the 25 months. For Evero, OS was 19.6 months, some of who were also likely surviving, as well. The OS of 25 months was clearly better with the Nivo group by this analysis. Nevertheless, half of all the 821 patients total died while on this trial from progressive disease. Of 183 of the 410 Nivo patients, 183 has died by 25 months, and 215 of the 411 Evero patients had died at 19.6 months.

There is no report of ongoing response here, but many went on to other meds, as explained below.

Median Progression Free Survival (PFS), measurable growth of disease, was 4.6 months for Nivo, 4.4 months for Evero. The median shows that half of each group, roughly 200 each had return of disease in less than 5 months! Again, these trial patients were pretty sick or at risk. All had been treated earlier, and had to stop previous treatments due to recurrence of disease. However, this shows a pretty quick return of disease or new growth from the base CT scan for nearly 65-70% of all patients.

One subgroup did a bit better than the 4 1/2 months median PFS. At six months after the start of treatment, there was a special subgroup was noted, about 1/3 of those patients–145 pts (35%) with Nivo, and 129 (31%) with Evero. Obviously they did not die or have Progressive Disease until after six months. The Nivo group had eventually had a median PFS of 15.6months, and the Evero group, 11.7 months. Their success pushed the median OS higher, especially for the Nivo group.

Obviously, there were some patients with far more aggressive disease in both groups, some dying before six months, and others not progressing to more disease until after six months. In contrast, nearly 1/3 of all the patients had PFS of 12-15 months, and much longer OS. What is the common characteristic in the most successful two groups in both arms of treatment? Not answered by this trial report.

The duration of treatment was longer with Nivo, and likely easier to tolerate. Since Nivo was given by IV every two weeks, the doses were most consistently received. Even so, 51% of them had dose delays, but no per dose reductions. Those people were seen by the medical team every two weeks.

The Evero group took oral meds, and 66% had dose delays or interruptions with 26% with at least one dose reduction. This would indicate that these meds could be hard to take, or perhaps lacking the same interaction with their medical team. Of course the Evero patients may have underreported how much of the medication they actually took!

However, the reported types of side effects were generally similar, but the more severe grade 3 and 4s effects in the Evero group.There were 2 treatment related deaths in the Ever group, none in the Nivo group.

POST PROGRESSIVE DISEASE

Even after the disease did progress, about half of patients in both groups stayed with their meds–despite ‘failing’, the researchers hopes that would continue to benefit, perhaps slowing the disease. In a local clinic setting or with a less experienced docs, their meds might have been stopped or changed. Afterall, those meds were no longer “working” and mets are growing. This approach is significant to consider, especially after multiple treatments. (The decision to keep giving a medication or increasing its dosage where tolerable is causing some changes in treatment in a number of the targeted therapies.)

Perhaps because of being in a trial or getting care than was more expert than most, one-half of patients chose to keep on the trial meds. Others crossed over to the med in the other arm or returned to existing non-trial meds. In some countries, there were likely fewer choices than in the US. There are no real stats as to survival for those on those who stopped taking the meds. It is reported that indicate that 55% of the surviving Nivo group and surviving 63% of the Evero group went on to other agents. About one-quarter of the Nivo group shifted to the Evero. Of the Nivo group, 36% shifted to axitinib.

Sadly, as per the chart in the New England Journal of Medicine, all these patients had died by 30-33 months post enrollment. However, it is again not clear what was effect, if any on that period from the non-trial drugs. Of the 227 who stopped Nivo for any reason, nearly half shifted to Evero. Of those who stopped Evero, 140 went to Axitinib.

DURABLE RESPONSES? HOW LONG? FOR HOW MANY?

The writers of the study say that there was a higher number of objective responses with Nivo vs Everolimus, and that many (of the Nivo group) “were durable”. There is no definition of ‘durable’. My question is “What equals durable?”. We patients really want a cure, but are very grateful for anything that pushes the cancer back, slows it, stops in from growing any further. Nevertheless, we do want those responses to last. The clearest reference to durable responses is a note that 32 of the Nivo patients and 6 of the Evero patients had a response that lasted more than 12 months. But in an unexplained statement, the median duration of treatment was just 5.5 months for the Nivo patients, 3.7 for the Evero group. It seems that there was not an extension available, or that the patients moved on to a different treatment or passed away.

CONCLUSIONS AND EDITORIALIZING AGAIN

It seems that Nivo is more helpful for some patients than others in this group previously been treated with other TKIs. This is NOT A SILVER BULLET. There would be greater value to know more about the molecular nature of the tumors of the responding and the non-responding patients. We desperately need to know for whom any of these drugs is likely to be more effective. The headlines that don’t discuss that challenge underserve us, as does the design of the trial that does not elicit the more nuanced, genomic data that could be forthcoming!

We all know that headline claims are more wonderful than the reality. The story of RCC medication development is that of more and more help in a difficult disease, making mixed progress, while the other researchers find out that RCC is really many diseases. Clear cell is probably better defined as being made up of four types, Papillary Type 1 and Type 2 being further divided into three Type 2, then there is chromophobe, clear cell papillary and the really odd versions of RCC. I known this, and so do you. But why don’t the researchers incorporate those definitions and monitor the patients with those various subtypes as they go forward?

Being diagnosed with kidney cancer is a stunner. Facing surgery and endless, oft unanswered questions changes your life. Patients with small tumors, easily removed, are often told not to worry about it coming back. Of course, there is ALWAYS the possibility that even small “I got it all tumors” can recur. Sadly, the current guidelines fail to catch about 30% of recurrences, using the 2013, 2014 guidelines. These guidelines were from an earlier era, where there were fewer small tumors found, so there was data lacking on long-term follow-up.

We patients ask? “Why not just take the meds that the patients with metastatic disease do? Wouldn’t that prevent it from coming back? If it works to fight the mets, why wouldn’t it prevent new ones from getting a foothold? “

Why not use the meds that they use now against metastatic disease? Why wouldn’t that work? Have they tested that idea?

In February of 2015, a study was released which comparing patient response to 1) sunitinib (Sutent),2) sorafenib (Nexavar), or 3) placebo (no real medicine). This three-arm study included 1,943 patients who had locally advanced clear cell and non-clear cell histology RCCs. They were thought to be at high-risk for recurrence of their cancer, and might benefit from “adjuvant” therapy. The researchers hoped that they would see a 25% improvement in time to recurrence of disease with the meds vs no meds.. That would means that the typical 5.8 years median Disease Free Survival (DFS) would go to 7.7 years.

Sadly, there was no benefit to taking the active drugs compared to the placebo. More sad is that the patients had side effects associated with the drug, referred to as “adverse events”. In fact, many dropped out of the active agent arms into the placebo arm, certainly knowing that the med they were taking were anti-cancer meds. Those “adverse events”, severe fatigue, hypertension or hand-foot reactions, were observed in those taking the active agents and rarely in the placebo patients.

The median time on the drugs was 8 months. That means half the patients were on drugs more than 8 months and half were on the drugs less than 8 months. Even those patients starting with lower doses of the drugs fared worse than the placebo group.

Despite taking the medications and enduring the side effects, the recurrence was about the same. With medication or without, these patients, as groups, did the same. Those taking the meds had Disease Free Survival of 5.6 or 5.7 years, similar to those not taking any real meds. There was no real added benefit to these patients. Certainly the quality of the life was affected by the side effects, and the constant reminder of the spectre of more cancer.

What can patients learn from this study?

The fear of recurrence is real. After all, the expected time until the disease progressed (love using that term for cancer!), was about 5 1/2 years. These patients were carefully monitored with CTs on a regular basis, which caught their recurrences as soon as possible. Had they not been in this trial, it is reasonable to expect that many would not have received those scans and not know of the recurrence as it happened.

The reality is that the typical patient may or may not continue to be monitored. Even those who passed the 5 1/2 year mark without recurrence may not realize that RCC can come back. Again, 30% of recurrences in small, non-metastatic disease are not caught. One can assume that the higher risk group in this trial would also be at risk for that level of recurrence.

Take-home message: At present, nothing has been shown to prevent recurrence of this locally advanced disease. Even the non-metastatic small tumors that have sent out invisible “wanna-be mets”, and no one can yet guess who is at the most risk.

The best approach is to monitor yourself and your general health and to demand CT scans, especially in the lungs, where metastatic RCC is most likely to start. That does NOT mean an x-ray, as those mets would have to be about 1/4″ in order to be seen. My own lung mets were under that size when first found, but there were hundreds of them, and they grew quickly. Not visible on an x-ray, but growing every day.

Despite the disappointing study above, the ASSURE study, more clinical trials are recruiting patients for similar studies using drugs that have already been shown to be less active than those in the ASSURE study. I would be cautious in getting into such a trial, and would spend my energies seeing that my monitoring is extended at least until 10 years past my surgery–even with those “got it all” primary tumors.

We all want the cure, the Complete Response (CR) that can lasts many months or years. Often we have to settle for some reduction in our tumors or mets, a Partial Response (PR). But even “Stable Disease” is welcome news. To get that cancer back in its cage, even for a time, is better than “Progressive Disease”. When the cancer is progressing, your life may be regressing, and that isn’t what you want to hear. That Progression Free Survival (PFS) has to start with stopping the cancer.

As complete and durable (ten years) responder to high dose interleukin 2 (HD IL-2), I welcome any discussions of “Clinical Benefit (CB)”. CB includes all the good responses with any cancer treatment, CRs, PRs, and SDs. We and our doctors need this information to make informed decisions about treatment, for IL2 or other meds. The value of Stable Disease has been ignored in many studies. Maybe there are lessons here for you and your doctors, especially about the under-utilized HD IL2.

There are few new studies about the use of HD IL2 following the approval of the targeted therapies. The ease of use of these agents, along with the desire not to send patients to specialty centers for IL2, limited its use. It was difficult to select patients, and the CR and PRs were relatively small in number. Doctors often did not discuss the possibility of a cure with their patients. Did patients also miss the chance for Stable Disease, and with it, a “Clinical Benefit”?

Patients in this study who did not have a CR, but whose cancer stopped growing benefited. That CB was not counted in terms of the approval of the drug, nor do doctors consider it in their recommendations. Should this possibility be discussed with patients? Most patients would surely answer, “Yes!” to that question.

The researchers recognize of the value of Stable Disease (SD) as an outcome, versus only Complete Response (CR) or Partial Response (PR). The usual outcome measures, Progressive Free Survival (PFS), or Overall Survival (OS), are noted, as isTime to Next Treatment (TNT). TNT implicitly recognizes that a failed or limited response will likely be followed by another treatment. Early on, there were no subsequent treatments, sad to say.

The original clinical trial which led to FDA approval of HD IL2 recognized only CR, which was 5%, with the median not reached during the trial, and PR, which was 14%. Study footnotes indicate that three of the PRs had surgery which rendered them disease free at the time of the publication. This would now be called a “salvage therapy”, and put them in the No Evidence of Disease (NED) class. A different analysis of this data would have upped the CRs some small percentage, and some SD would also have been found.

Also the definition of PR was 50% or greater reduction in measurable tumor size, the sum of the perpendicular diameters of all lesions, with no new increase of sizeof any other mets. Far less strict measurements of PR were used in the targeted therapy trials, with a 30% tumor reduction defined as a Partial Response.

With those definitions in mind, note that there are CRs in 11% of patients, with a PR in an additional 6% of patients. Most important is the SD category, which was achieved for 31% of all patients. This total of 47% is described for the group as being of Clinical Benefit (CB). Certainly patients value the responses of SD, which seems to have provided slightly over one year versus 3-4 months benefit to those who did not have SD.

When comparing the value of Objective Response (OR) with its median of 1616 days to that of Stable Disease (SD) measured as 1476 days, one can clearly see the value of achieving Stable Disease. Unfortunately, those patients with Progressive Disease, or with responses Not Evaluable (NE), showed OS of 365 days.

Patients should be aware of these definitions and the impact the lack of parallel comparisons in making these critical decisions. Ten years ago, the patients reminded one another to stay alive until the next treatment. Having Stable Disease made that possible. Let’s apply the same tests to all the available treatments when making these life-changing choices of treatment.

Background: HD IL-2, an immunotherapy, is a standard of care for a select group of patients (pts) with mRCC. Generally objective response (OR) rates, i.e. complete response (CR) + partial response (PR), of 16-20% are discussed with pts, but not disease stabilization (SD). Recent data suggest that cancer immunotherapy may improve survival without inducing OR. Thus, treatment with HD IL-2 may provide survival benefit to an additional group of pts not experiencing OR, but only SD as the best response. Here we report CB (OR+SD), and specifically report outcomes of cc mRCC pts experiencing SD as the best response, on treatment with HD IL-2.

Methods: All sequential cc mRCC pts treated with HD IL-2 at the University of Utah Huntsman Cancer Institute from 2000-2012 were included. Pts were evaluated for best response, progression-free survival (PFS), time to next treatment (TNT) and overall survival (OS). Two practitioners independently reviewed HD IL-2 response with discrepancies adjudicated by a third reviewer.

Results: 85 pts, 79% male, were identified with a median age of 56 (range 32-76) years. Pts belonged to the following MSKCC risk categories: 11 (13%) good, 70 (82%) intermediate, and 4 (5%) poor risk. A CR was identified in 9 (11%), PR in 5 (6%), SD in 26 (31%), progressive disease (PD) in 38 (45%), and unknown/not evaluable (NE) in 7 (8%) pts; yielding a clinical benefit in 40 (47%) pts. The median PFS, TNT, and OS in these individual groups of pts are compared in the table.

Conclusions: A clinical benefit of HD IL-2 was achieved in nearly half of all clear cell mRCC patients. OS was not significantly different in OR and SD groups. Even though OR favorably determine outcomes, SD is also an important response criterion, and may be discussed during counseling patients for treatment with HD IL-2.

When you are suddenly thrust into the medical world, unwillingly and without any kind of road map, you are surrounded by poorly marked turns, meaningless abbreviations and the sudden shift in the dialect. The Wellness Center is usually about having lost one’s “wellness”, a word used only in the medical world, and not by real people.

Pressed to make decisions that may change your life, for the better or worse, you can be confused by those clever new words, some from the marketing people (see above) and others from the clinical side. It is critical to understand how familiar words get reworked to explain new concepts. Such explanations rarely reach patients, who are numbed and deafened after a shocking diagnosis. And in the medical “new-speak”, those same patients may be told that this is the time in which they must take charge of their health, and make wise decisions quickly and correctly. I find this a cynical and self-serving approach, as rarely is any real education offered in the language of the patient.

In kidney cancer, we have been blessed with new drugs these past eight years, but have no clear way to determine which of these agents might be of benefit to any of us. On top of the shock of diagnosis, the patient is thrust into a guessing game. Even the doctor is forced to play along, and often neither party knows the rules or the chances to win. The doctor may recognize the vocabulary used in this new guessing game, but the patient does not. Words which have meaning in day to day life don’t work the same. Even some of the goals of the game are unclear to the patient. Wait! You probably think that being cured is the goal. you

For example, we patients think that “progress” is good, but that is not true in cancer. Progression is the goal of the cancer, so Progression Free Survival (PFS) measures the time between treatment and when the cancer is on the visible move again. The word “visible” is important here, as that is a reminder that cancer does not just start at a size or style to match the sensitivity of imaging. X Rays cannot see things as small as a CT scan can. Bone scans see bone mets better than other scans and so on.

In reading clinical trials, you will encounter “durable” to explain how long a median PFS can be. It may be described as remarkably durable, but in the pre-patient world, we would think that is pushing into years and years. In reality is may be 15- 18 months. We happily grasp at any more months than the non-treatment reality may be, but be aware of your and your doctor’s expectations in durability.

“Durable response” is surely what we want, but that is not translated to a cure, which might be the patient’s interpretation. When you hear that, do ask for clarification, “How long does that response last? What do you mean by ‘durable’? What do we do after the duration of response comes to a stop?”

Having a firm grasp of this term and all others is an absolute necessity, and even if that is hard–in the real sense–it will be worth it to you. You will have greater understanding of the treatments, the disease process, and a bit more sense of where you are.

More on these topics later, but do track the language, and remember than you still speak the old language. At the very least, be ready to question anything that has that new dialect sound to it!

I was dying ten years ago. My kidney cancer had moved into my lungs, threatening to choke me to death.The tumor and kidney were gone, but 100s of tiny lung metastases were growing. Lucky to get an FDA-approved immune therapy, high dose interleukin 2, my own immune system was revved up so as to destroy the cancer. Thus, I am intrigued by all things about the immune system and cancer research. “Adaptive immunity in cancer immunology and therapeutics”is one of the most comprehensive explanation of the tumor cell/immune system interactions–that I can somewhat(!) understand.

My summary is below, a more patient-friendly version. Don’t hesitate to take on the original, via the link! It is just the kind of article to take to your doctor to discuss immune response meds/treatments. It begins with the “abstract”, a summary of the information to follow.

Abstract: The vast genetic alterations characteristic of tumours produce a number of tumour antigens that enable the immune system to differentiate tumour cells from normal cells. Counter to this, tumour cells have developed mechanisms by which to evade host immunity in their constant quest for growth and survival. Tumour-associated antigens (TAAs) are one of the fundamental triggers of the immune response. They are important because they activate, via major histocompatibility complex (MHC), the T cell response, an important line of defense against tumourigenesis. However, the persistence of tumours despite host immunity implies that tumour cells develop immune avoidance. An example of this is the up-regulation of inhibitory immunemonoclonal antibodies in clinical practice have been developed to target tumour-specific antigens. More recently there has been research in the down-regulation of immune checkpoint proteins as a way of increasing anti-tumour immunity.”

Immune Responses in Tumors—A Quick Summary by Peg

Since cancer cells are genetically different from normal cells, they also produce different substances—antigens—which can make them more noticeable to the immune system. Any antigen will generate a response from the immune system—think how the body reacts to an infection, an insect sting or a splinter.
Antigens trigger the immune system into action, keeping abnormal cells from taking over the system—most of the time. To grow, tumor cells develop inhibitory responses to limit or down-regulate those immune responses. An over-active immune response can be problem, well-known to those with severe allergies or auto-immune diseases like lupus. Keeping the proper balance is the norm for the immune system, despite ongoing external and internal changes

Using knowledge of these interactions to support the immune system, researchers have develop agent/medications. These are intended to strengthen the beneficial responses, and to prevent the tumors from suppressing or down-regulating those desired responses. Some monoclonal antibodies can effectively target these tumor-specific antigens and trigger tumor death or inhibit such growth. Some of these new agents include bevacizumab (Avastin), rituximab (Rituxin), alemtuzumab (Campath or Lemtrada), bortezomib (Velcade), denosumab (Xgeva) and trastuzumab (Herceptin), among many others, and for a variety of cancers.

Be aware that these agents may be called by the brand name, as Sutent, or the scientific name, as sunitinib, and may have several brand names for different cancers. Just another new challenge to all of us newbies.

Tumors exist with a system of structures, various types of cells and with a chemical signaling process. These shifts away from the normal cells and organs produce tumor antigens. The immune system notices the antigens and works to destroy the foreign cells. Then the tumors shift to counter the immune response in an endless signaling battle. It is a dynamic “fail-safe” system, with multiple checks and balances, work-around pathways, evasive signaling, and constant testing to maintain itself. When this system does fail, a tumor can be established and move to different sites.

Solid tumors have a tumor core, a margin that is invading into a healthy structure–blood vessels or layers of an organ–and lymphoid components. This can vary patient to patient, despite the seeming similarity of tumors, and vary from one metastatic tumor site to another. Inside the tumor will be the immune-cell types–macrophages, dendritic cells, natural killer (NK) cells, mast cells, B cell, and T cells. Different immune cells can be found in different parts of the tumor, and the variation and the density of these cells may play a role in clinical response. It may be that this reflects the robust nature of the natural response to the tumor invasion, or reflect that the system is being overwhelmed by the tumor. Others think that the infiltration of immune cells can be utilized the support of the treatments given to the patient.
The linked journal article goes into detail as to the various types of responses, including adaptive immunity, immune editing and immune evasion. In summary, there are numerous approaches to limit tumor growth within the complex system of antigens and immune responses.
As immune cells infiltrate a tumor, that infiltration can be measured. What is the meaning of a higher or lower level of immune cell infiltration? The following paragraph sums up the challenge of using tumor infiltration as a marker of prognosis or treatment response.
It is a commonly held belief that infiltration of immune cells into tumor tissues and direct physical contact between tumor cells and infiltrated immune cells is associated with physical destruction of the tumor cells. That can reduce the tumor burden, and improve prognosis. An increasing number of studies, however, have suggested that aberrant infiltration of immune cells into tumor or normal tissues may promote tumor progression, invasion, and metastasis. Neither the primary reason for these contradictory observations, nor the mechanism for the reported diverse impact of tumor-infiltrating immune cells has been elucidated, making it difficult to judge the clinical implications of infiltration of immune cells within tumor tissues. J Cancer 2013; 4(1):84-95. doi:10.7150/jca.5482

Tumor Infiltrating Immune Cells—a Good Sign or Not?

If the immune system is at work, immune cells infiltrate the tumor to work directly against the tumor cells, is the tumor destroyed? Does the body naturally destroy the tumor? Does the patient benefit from medical treatments which support the immune system? Unfortunately, the presence of the tumor-infiltrating cells can mean very different things, with a better prognosis in one type of cancer, and a poorer prognosis in another.

Monoclonal antibodies can target antigens in blood cancers and solid tumors. In blood cancers, antibodies counter several cluster of differentiation (CD) markers, and in solid tumors, growth factors such as EGFR (epidermal growth factor receptor) or angiogenesis factors, such as vascular endothelial growth factor (VEGF). The mechanisms of action can lead to direct cell death, or simply impede its growth or inhibit checks on the immune response.

Normal cells are naturally programmed to die, but cancer cells do not “follow the program”. When certain proteins on the surface of cells bind with one another, the expected immune response is inhibited. These anti-PD-1 (anti-Programmed Death-1) proteins bind with other proteins, the binders or ligands, PD-L1 and PD-L2. Studies indicated these agents can help the immune system, with some disease stabilization or tumor shrinkage. Recent trials show some response by 20-25% of patients, some of whom had failed previous treatments. Some responses lasted more than a year. In a few cases, some responses were lasted for a period after stopping the medications. Newer trials will likely combine several of these therapies. This is not without risk, as some had severe side effects, and several patients died from such side effects.

Nevertheless, the earlier successes with this approach and the increased knowledge of the various immune responses to be targeted will continue, especially in combination studies. This work will have impact on existing immune therapies, as does the more integrated approach to cancer treatment.

I welcome any comments and corrections, and remind you that I am a patient, and am not a medical professional. My goal is to help educate other patients to receive the best understanding of their illness and best possible treatment.

“Now what?” may be the first coherent question a newly diagnosed cancer patient asks. Maybe the smarter version of that is “What–when and why?” And your doctor had better have a good answer, as to the treatment, the when and the why.

We cancer patients usually get surgery “first”, even when the disease has spread. Primary surgical strike and then a clean-up operation, in the ‘war on cancer’ parlance, we think–when we can think. “But which is the best and first clean-up approach?” we must ask. “What works the best? What can I take with my other health problems? Where does surgery or radiation fit in this scheme? What does the doctor favor and why? Where do I get this treatment? And then what?”

Treatments and their sequence are often chosen with little reliance or clarity as to the data. But some light was shed today at ASCO (American Society of Clinical Oncology). It released a comparison of the sequencing of High Dose Interleukin2 (HD IL2) and of targeted therapies for metastatic RCC. Which should come first?

It shouldn’t be a high-stakes gamble to choose a medication, as no one can guarantee any results–with any of the meds. You take a chance with any drug, so which do you start wi We may be closer to a logical approach in sequencing these drugs. Sequencing of these highly different medications has measurable effect on overall survival (OS)—and to patients’ lives. That sequencing is critical and certainly can extend life, even when treatments fail, as they so often do.

A retrospective study of 97 US patients who received HD IL2, before or after a targeted therapy was just presented at ASCO. These patients were followed for a median duration 37 months–half more than 37 months, half fewer than 37 months. Of that group, 22% had either a partial (14%) or complete (8%) response to HD IL2. (No specifics as to what was a “partial” response, perhaps a 30% shrinkage of the total tumor burden). In addition, another 24% of patients had Stable Disease(SD). Thus, nearly half of these patients benefited from having had HD IL2.

Stable disease is better than progressive disease, as any patient knows, though it was rarely measured in older trials. Though we patients really want a cure, we do want to be around for the next treatment, to have a surgery or ablation to remove the “stable” tumor, or to try another medication.

Of these 97 patients, 82 received HD IL2 before any targeted therapy. Another 15 patients had HD IL2 following a TKI therapy. That timing made an important difference. HD IL2 followed by the TKI, showed a median Overall Survival (OS) of 61.8 months. The OS of those with the TKI before the HD IL2 was 48 months. A median, not an average, so half lived longer, half lived shorter than the quoted medians.

A pre-2006 NCI (National Cancer Institute) series showed a 19 month median survival for HD IL2 alone, and a similar 19 months for the use of targeted therapy alone. Using the two in sequence dramatically improved OS, especially when HD IL2 was first line of treatment. Obviously things have improved, though it can be very difficult to compare older trial data, as so many variables are different–including the type of RCC the patients had as they entered the trials.

Several points can be made from this study. First, no therapy should be examined only as to Complete or Partial Response. Stable Disease also adds to Overall Stability. To stop the tumor from growing, even if for a period of time, is valuable to patients and can prep them for the next anticipated treatment. Sure beats tumor growth!

Second, therapies should be chosen to maximize their impact on the overall survival of the patient. Some patients will naturally be precluded (or delayed) from surgery, or taking one drug due to existing co-morbidities, due to heart disease or liver damage. For those post-op patients, likely to tolerate the side effects of HD IL2, it should be given in a first-line setting.

The most critical variables that impact patients are the recommendations and expectations of the physician. Most patients are not even told about HD IL2 treatment, or it is dismissed casually as “not for you”. Others are told to wait until more mets emerge, with some weird theory that waiting for more trouble is a good thing! Many nephrectomy patients are not monitored post-operatively, despite the risk of mets. This is surely an indicator of the lack of knowledge by urologists. Still others are told that the disease has spread, and that nothing can be done–also untrue.

The rarity of RCC and its variants leaves most physicians unaware of all options in the field, and how to any one might suit for a particular patient. Most oncologists to whom patients are referred, have little or no experience treatmenting for RCC, or may not access to academic centers for support until it is too late. Even the pathology of the primary tumor and later metastases may be questionable, adding to the challenge of care.

With the dramatic changes in the RCC field, this is to be expected—but not tolerated. The patient may have to provide his physician with the data that can extend or save his life, which is a sad but realistic commentary on the field today.

Most people are not surprised that there is no ONE thing called cancer. Tumors in all the organs or invasive cells in the blood or bones are referred to as cancer, but start when cells go wrong, whatever the cause. As soon as you are told you cancer, whatever it, the quest begins to find out exactly which cancer it is. With kidney cancer, or its more melodious name, renal cell carcinoma, there seem to be endless variations on what may be called kidney or renal cancer. To treat it requires a very careful analysis of what is really is, starting with the pathology of the tumor when it is biopsied. With kidney cancer that biopsy is usually done after surgery for the tumor. That biopsy will describe the shapes and type of cell in the tumor, which can be mix of types. And then the real work begins.

A recent article in “European Urology” reviewed the mix of HEREDITARY renal cancers, those that arise due to one’s background. More common are the “sporadic” kidney cancer that could arise out of the blue or in response to some environmental toxin. There are ten Heredity Renal Cancers, or HRCs. My goal is to alert the reader to the possibility that his cancer might be one of these. This would affect treatment, and may suggest the need to test family members.

If you have kidney cancer or RCC, you may be familiar with “clear cell” or “papillary” to refine the description of the cells in the tumors. This may not be the whole story, as those HRCs—the hereditary kinds—may manifest a mix of ways, including as clear cell or papillary histology.

The most common HRC is Von Hippel-Lindau (VHL) disease, with both benign or malignant tumors. RCC can be found in a 24-34% of VHL patients, appearing at mean age 39 years (far younger than non-heredity RCC), and often with multiple tumors and in both kidneys. Cysts which appear not to be malignant must be watched–they have the potential to become malignant over time. Generally they are managed based on the size of the largest of these lesions. Clear cell RCC is the one VHL-related subtype.

Hereditary papillary renal carcinoma (HPRC) is rarer, and typically occurs later in life. Papillary tumors are the only phenotype with HPRC, and patients often develop numerous tiny tumors, 1000 or more. These tumors are considered type 1 papillary renal cell carcinoma (pRCC) with a low nuclear grade, monitored with CT scans, and some do metastasize, though this is rare. The MET gene is implicated in the growth of these tumors.

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is newly identified as a HRC. Rarely do patients develop RCC, but are susceptible to developing multiple leiomylomas, which are generally benign. When there is early onset of HLRCC, then RCC is found in about 20% of those patients. These tumors can be aggressive, and about 2/3 display a papillary pattern. Such tumors tend to be hyper-vascular.

Birt-Hogg-Dube (BHD) syndrome is quite rare, about 1 in 200,000 people, and thereby likely under diagnosed. This raises the risk of developing kidney tumors, which occurs in 25-35% of BHD patients, and at mean age of 50. These tumors have varying histologic subtypes, generally chromophobe RCC or hybrid variants. And there can be variants in the same tumor or within the kidney. There is a risk of metastases, though rare. The characteristic skin lesions of BHD syndrome are not malignant.

Even more rare is Tuberous Sclerosis Complex (TSC), which can manifest itself in renal lesions, cysts and occasionally, RCC, the latter at a young, average age 28. Neurologic complications can accompany this syndrome.

SDHB-associated paraganglioma/phaeochromoytoma is another heredity condition which may give rise to a mix of renal tumor, including clear cell RCC, chromophobe RCC and oncocytomas, i.e., a mix of histologically different types.

An HRCmay be suspected in patients with a family or individual history of renal tumors, in the instance of both kidney having tumors, or one kidney having multiple tumors or in early-onset renal tumor, i.e., under 50 years of age.

Clinical diagnosis can be further refined by genetic testing, and thorough review by an experienced uropathologist is fundamental to the diagnosis. First consideration would be a VHL analysis and genetic analysis of SDHB and FLCN genes, as warranted. Patients with type 1 papillaryRCC should be considered for MET analysis. The presence of clinical symptoms related to any of the syndromes will guide the gene screening. Testing on family members may well be warranted.

With these cancers, it is possible to have multiple lesions and affect both kidneys. Thus, treatment should preserve renal function and control the risk for metastases. Use of ablation to retain maximum renal function may be preferable to partial nephrectomies, for example.

Though these heredity renal cancers arise in a different manner than the more common sporadic RCC, the study of the molecular pathways provide some insight into new therapies for those patients as well. Thanks always to those researchers who help in this struggle for information, as that is essential to provide treatments.